The angiogenic switch involves the formation of new blood vessels (neovasculature), and is a hallmark of cancer emergence and progression (Folkman, N Engl J Med 285, 1182 (1971); Hanahan and Folkman, Cell 86, 353 (1996); Carmeliet and Jain, Nature 407, 249 (2000)). In adults, neovasculature formation relies on the sprouting and cooption of proliferating endothelial cells from adjacent preexisting host vasculature. More recent investigations suggest that the adult bone marrow (BM) is a source of cells that contribute significantly to postnatal angiogenesis (Kopp et al. Curr Opin Hematol 13, 175 (2006); Carmeliet, Nature 438, 932 (2005)). Of the BM-derived cells, much focus has been directed on the proangiogenic hematopoietic mural cells that are recruited to the perivascular sites within the tumor bed (Kopp et al., Curr Opin Hematol 13, 175 (2006); Carmeliet, Nature 438, 932 (2005); Coussens and Werb, Nature 420, 860 (2002); Pollard, Nat Rev Cancer 4, 71 (2004)). Several populations of BM-derived hematopoietic cells have been reported to contribute to tumor angiogenesis. These include tumor-associated macrophages (TAMS) (Pollard, Nat Rev Cancer 4, 71 (2004); Lin et al., J Exp Med 193, 727 (2001)). Tie2-expressing monocytes (TEMs) (De Palma et al., Cancer Cell 8, 211 (2005)), VEGFR1-positive myeloid progenitors (Lyden et al., Nat Med 7, 1194 (2001)), recruited bone marrow-derived circulating cells (Grunewald et al., Cell 124, 175 (2006)), PDGFRβ+ pericyte progenitors (Song et al., Nat Cell Biol 7, 870 (2005)), vascular leukocytes (Conejo-Garcia et al., Blood 105:679-681 (2005), and infiltrating neutrophils (Nozawa et al., Proc Natl Acad Sci USA 103, 12493 (2006)).
In addition to the perivascular contribution of BM-derived hematopoietic cells, it has been proposed that the BM-derived endothelial progenitor cells (EPCs) may provide an alternative source of endothelial cells that contribute to neovessel formation (Kopp et al., Curr Opin Hematol 13, 175 (2006); Lyden et al., Nat Med 7, 1194 (2001); Urbich and Dimmeler, Trends Cardiovasc Med 14, 318 (2004); Khakoo and Finkel, Annu Rev Med 56, 79 (2005); Asahara et al., Embo J 18, 3964 (1999); Rafii, et al., Nat Rev Cancer 2, 826 (2002)). However, the true identity of EPCs and their relative contribution to neovasculature formation has been controversial. Extensive variability in EPC contribution to vessel formation has been described. For instance, contribution as high as 50% (Lyden et al., Nat Med 7, 1194 (2001); Garcia-Barros et al., Science 300, 1155 (2003)), to as low as 5-20% (Peters et al., Nat Med 11, 261 (2005); Rajantie et al., Blood 104(7):2084-6 (2004); Machein et al., Brain Pathol 13, 582 (2003)), and in some cases undetectable levels (De Palma et al., Cancer Cell 8, 211 (2005); De Palma et al., Nat Med 9, 789 (2003); Gothert et al., Blood 104, 1769 (2004); Ziegelhoeffer et al., Circ Res 94, 230 (2004); Voswinckel et al., Circ Res 93, 372 (2003); He et al., Cancer Res 64, 3737 (2004)) have been reported. Thus, it remains unclear whether bone marrow-derived EPCs play a significant role in tumor neoangiogenesis and hence serve as a valid target for cancer therapy.